3-amino-propyloxyphenyl derivatives, their preparation and pharmaceutical compositions containing them

ABSTRACT

##STR1## wherein (A) R is O(CH 2 ) 2  O-R 3  and 
     (a) R 1  and R 5  are hydrogen and R 3  is n-propyl, isobutyl, cyclopentylmethyl, benzyl or 2-(p-fluorophenyl)ethyl; 
     (b) R 1  is fluorine and R 5  is hydrogen and R 3  is n-propyl; 
     (c) R 1  is methyl and R 5  is hydrogen and R 3  is cyclopropylmethyl; 
     (d) R 1  is cyano and R 5  is hydrogen and R 3  is n-propyl; 
     (e) R 1  is hydrogen, R 5  is methyl and R 3  is alkyl of 2 to 5 carbon atoms, cycloalkylmethyl of 5 to 7 carbon atoms in the cycloalkyl part thereof or --(CH 2 ) n  --R&#39; wherein n is 0, 1 or 2 and R&#39; is phenyl or monofluorophenyl; or 
     (B) R is hydroxy, R 1  is fluorine and R 5  is hydrogen, and their physiologically hydrolysable derivatives, in which at least one hydroxy group is in esterified 
     form, and their salts, elicit highly cardioselective beta 1 adrenoceptor blockade, and in most cases cardiospecific blockade, and relevant cardiotonic activity. These compounds can be used as therapeutic agents. One obtains these compounds by 3-amino-2-oxypropylation of the respective substituted phenol.

This is a continuation of application Ser. No. 294,961, filed Jan. 9, 1989, now abandoned, which is a continuation of application Ser. No. 807,068, filed Nov. 21, 1985, now abandoned.

The present invention relates to compounds of Formula I, ##STR2## wherein A) R is O(CH₂)₂ O--R₃ and

(a) R₁ and R₅ are hydrogen and R₃ is n-propyl, isobutyl, cyclopentylmethyl, benzyl or 2-(p-fluorophenyl)ethyl;

(b) R₁ is fluorine and R₅ is hydrogen and R₃ is n-propyl;

(c) R₁ is methyl and R₅ is hydrogen and R₃ is cyclopropylmethyl;

(d) R₁ is cyano and R₅ is hydrogen and R₃ is n-propyl;

(e) R₁ is hydrogen, R₅ is methyl and R₃ is alkyl of 2 to 5 carbon atoms, cycloalkylmethyl of 5 to 7 carbon atoms in the cycloalkyl part thereof or --(CH₂)_(n) --R' wherein n is 0, 1 or 2 and R' is phenyl or monofluorophenyl; or

B) R is hydroxy, R₁ is fluorine and R₅ is hydrogen, and their physiologically hydrolysable derivatives, in which at least one hydroxy group is in esterified form.

Physiologically hydrolysable derivatives are derivatives, in which under physiological conditions the esterified hydroxy groups are deesterified to give the corresponding hydroxy compound.

An example of an esterified compound is shown as Formula E. ##STR3## wherein R, R₁ and R₅ are as defined above and R_(e) is alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono- or independently disubstituted in the phenyl ring by halogen of atomic number of from to 35, or mono- or independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.

Preferred are compounds in which a hydroxy group is not esterified.

In accordance with the invention the compound of the invention may be obtained by a process which includes the step of appropriately 3-amino-2-oxypropylating a corresponding compound of Formula II, ##STR4## wherein R and R₁ are as defined above or a precursor form thereof.

The process step of the invention may be effected in conventional manner for the production of analogous 3-amino-2-oxypropoxyaryl compounds.

The choice of the most appropriate variants should, of course, take into account the reactivities of the substituents present.

A precursor form of the compound of Formula II is a compound capable of being converted into a compound of Formula II, e.g. by appropriate etherification, aromatic substitution and/or deprotection.

When R is --OCH₂ CH₂ O--R₃, a precursor form is for example a corresponding compound wherein the moiety --OCH₂ CH₂ O--R₃ is replaced by a hydroxy group, in optionally protected form.

Benzyl, methyl or 2-tetrahydropyranyl, preferably benzyl, are examples of a protecting group on for example a hydroxy substituted phenyl ring.

Thus, the process step of invention may be effected in more than one stage. For example, a compound of Formula II in protected form may be used, or a 3-amino-3-oxypropyl moiety in protected form may be introduced, and subsequently, after 3-amino-2-oxypropylation has been effected, the protecting group present may be split off.

In one form of the process according to the invention, the 3-amino-2-oxypropylation is effected in two main process stages.

In the first process stage a group CH₂ R_(x) wherein R_(x) is a group capable of reacting with a primary amine to give a 2-amino-1-hydroxy ethyl group is introduced by O-alkylation in the one position into a compound of Formula II to give a corresponding compound of Formula III. ##STR5## wherein R₁ and R_(x) are as defined above.

In the second process stage a compound of Formula III is aminated with a corresponding compound of Formula IV, ##STR6## wherein R₅ is hydrogen or methyl, and where required at least one hydroxy group in a resulting compound of Formula I is appropriately esterified.

The O-alkylation process stage in the one position may be effected in a manner known for the production of analogous ethers. A compound of Formula II preferably is reacted in an ionic form.

The amination process stage may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds. For example, R_(x) may be a group of Formula ##STR7## or a derivative of this group for example a group of Formula --CH(OH)CH₂ --L wherein L is chlorine, bromine or a group R_(y) SO₂ O-- wherein R_(y) is phenyl, tolyl or alkyl. L is preferably chlorine. The reaction is preferably effected in ethanol or in an appropriate ether such as dioxane. Optionally an excess of the amine may be used as solvent. Alternatively the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20° to about 200°. Conveniently the reflux temperature of the reaction mixture if a solvent is used.

The optional esterification in a resultant compound of Formula I may be effected in a manner known for the production of analogous esters, if necessary, using selective conditions when other reactive groups, for example hydroxy or amino are present.

The compounds of the invention may exist in free form, i.e. normally as a base, or in salt form. Free forms of the compounds of the invention may be converted into salt forms, for example acid addition salt forms, and vice versa, in a conventional manner. Suitable acids for acid addition salt formation include hydrochloric, malonic, succinic, oxalic and fumaric acid.

In the compounds of the invention the carbon atom in for example the 2 position of the 3-amino-propoxy side chain is asymmetrically substituted and when R₅ is methyl the carbon atom on the alkylene side chain is also asymmetrically substituted. The compounds may thus exist in the racemate form or individual optical isomer forms. The preferred optical isomer has the S-configuration at the asymmetrically substituted carbon atom of the 3-amino-propoxy side chain and when R₅ is methyl on the alkylene side chain the preferred conformation has the R-configuration. Individual optical isomer forms may be obtained in conventional manner, for example by using optically active starting materials or by fractional crystallization of racemate salts using optically active acids.

In so far as the preparation of any particular starting materials is not particularly described, this may be effected in conventional manner. In the following examples all temperatures are in degrees centrigrade and are uncorrected.

EXAMPLE 1 1-(2-Methyl-4-(2-cyclopropylmethoxyethoxy)-phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino) ethylamino)-2-propanol

3.0 g of 4-(2-(cyclopropylmethoxy)ethoxy)-1-(2,3-epoxypropoxy)-2-methylbenzene is refluxed with 2.3 g of N-(2-amino-ethyl)tetrahydropyran-4-carboxamide (obtained by reacting tetrahydropyran-4-carboxylic acid ethyl ester with ethylenediamine) in 100 ml methanol for three hours, with stirring. The resultant oil is chromatographed over silica gel with methylene chloride/ethanol/conc. ammonia (150:27:3). Late eluting fractions containing the title compound is taken up in ethylacetate and 2M NaOH solution and washed with water. The organic phase is dried over magnesium sulfate and following removal of solvent the title compound is recrystallized from methanol/ether (M.P. 80°-83°).

The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted withepichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).

EXAMPLE 2 1-(2-fluoro-4-(2-propoxy-ethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino) -2-propanol

Method A: N-(2-aminoethyl)-tetrahydropyran-4-carboxamide is reacted with 1-(2,3-epoxypropoxy)-2-fluoro-4-(2-propoxyethoxy)benzene giving the title compound (melting point 107°-108°-from ethyl acetate).

The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.

Method B: 2.1 gm of 1-(2-fluoro-4-hydroxyphenoxy)-3-(2-(tetrahydropyran-4-yl-carbonyl-amino) ethylamino)-2-propanol is reacted with 0.15 gm of sodium hydride in dimethylformamide at room temperature. After 30 minutes stirring at room temperature 1.5 gm of 2-bromoethyl propylether in dimethylformamide is gradually added and maintained at 100° for 16 hours. Excess sodium hydride is removed with methanol and the mixture evaporated. The residue is extracted with methylene chloride and water, and the organic layer chromatographed over silica gel with methylene chloride/ethanol/ammonia 35% in water (90:9:1). The title compound is obtained (M.P. 107°-108° from ethyl acetate).

From the appropriate compounds of Formula III wherein R_(x) is ##STR8##and the appropriate compound of Formula IV the examples numbered 3 to 8 of Formula I are obtained in analogous manner to examples 1 and 2.

    ______________________________________                                         Example                               M.P.                                     No.    R.sub.1                                                                               R.sub.5                                                                              R                 (as base)                                ______________________________________                                         3      H      H     O(CH.sub.2).sub.2 OCH.sub.2 CH.sub.2 CH.sub.3                                                    108-110°                          4      H      H     O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   111-113°                          5      H      H                                                                                     ##STR9##         114-115°                          6      H      H                                                                                     ##STR10##        92-94°                            7      H      H                                                                                     ##STR11##        107-108°                          8      CN     H     O(CH.sub.2).sub.2 OCH.sub.2 CH.sub.2 CH.sub.3                                                    104-107°                          ______________________________________                                    

EXAMPLE 9 (S)-1-(4-(2-propoxyethoxy)phenoxy)-3((R,S)-2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol

3 g of (S)-1-(2,3-epoxypropoxy)-4-(2-propoxyethoxy) benzene is added to 2 gN-((R,S)-2-amino-1-methylethyl)tetrahydropyran-4-carboxamide at room temperature and warmed to 50° and kept for 14 hours with stirring. The product is purified over silica gel with methylene chloride/methanol (95:5) (methylene chloride with 10% NH₃) as eluent. The title compound is obtained (M.P. 82°-86°-from ether/hexane; [α]_(D) ²⁰ =-0.55° (c=1.9/methanol)).

The amine starting material is obtained by reaction of 1,2-diaminopropane and tetrahydropyran-4-carboxylic acid ethyl ester without a solvent at 90°, followed by two chromatographic purifications on silica gel using

(a) acetone/ethylacetate/conc. NH₃ (5:5:0.5) and

(b) methylene chloride/methanol (7:3) (methylene chloride containing 10% NH₃)

One obtains N-((R,S)-2-amino-1-methylethyl)tetrahydropyran-4-carboxamide asan oil.

The epoxide starting material is obtained as follows:

(a) Hydroquinone monobenzyl ether is reacted with 2-bromoethyl-n-propyl ether in aqueous sodium hydroxide and then purified over silica gel with toluene as eluent. The middle fraction gives 1-benzyloxy-4-(2-propoxy-ethoxy)benzene (used without further purification).

(b) The ether obtained under (a) is hydrogenated over 10% palladium on activated charcoal giving as an oil 4-(2-propoxyethoxy)phenol.

(c) The phenol obtained under (b) is reacted in the absence of a solvent and in the presence of a catalytic amount of piperidine with (-)-(2,3-epoxypropoxy)-methylbenzene at 120°. After purification bychromatography (+)-1-(3-benzyloxy-2-hydroxypropoxy)-4-(2-propoxyethoxy)benzene is obtained; [oil; [α]_(D) ²⁰ =+3.2° (c=1.5/methanol)].

(d) The ether obtained under (c) is hydrogenated with 10% Palladium over activated charcoal giving (+)-1-(2,3-dihydroxypropoxy)-4-(2-propoxyethoxy)benzene; [oil; [α]_(D) ²⁰ =+4.5 (c=1.9/methanol)].

(e) The diol obtained under (d) is reacted with p-toluene sulfonyl chloridein pyridine giving (-)-1-(3-toluylsulfonyloxy-2-hydroxypropoxy)-4-(2-propoxyethoxy)benzene [oil; [α]_(D) ²⁰ =-5.3° (c=1.9/methanol)].

(f) The tosylate obtained under (c) is converted to (+)-1-(2,3-epoxypropoxy)-4-(2-propoxyethoxy)benzene with sodium methoxide [oil; [α]_(D) ²⁰ =+6.6° (c=2.1/methanol)].

Likewise from step (c) (-)-(2,3-epoxypropoxy)methylbenzene is obtained by reaction of (+)-3-benzyloxy-1,2-propandiol-1-tosylate in methanol at 0°-3° with sodium methoxide (oil; [α]_(D) ²⁰ =-10.8°, c=1.8/methanol).

EXAMPLE 10 (S)-1-(4-(2-propoxyethoxy)phenoxy)-((R)-2-(tetrahydropyran-4-ylcarbonylamino)-1-methylethylamino) -2-propanol

This compound is obtained as for Example 9 except that N-((R)-2-amino-1-methylethyl)tetrahydropyran-4-carboxamide is used insteadof the racemate.

The amine reactant is obtained from t-butoxycarbonyl-(D)-alaninamide which is dehydrated with p-toluolsulfonyl chloride in pyridine at 50° for4 hours to give (R)-2-tert-butoxy-carbonylamino propionitrile which is thenreduced with Raney-nickel in ethanol (20% saturated with NH₃) to give (R)-2-tert-butoxycarbonyl amino propylamine. Reaction with tetrahydropyran-4-carboxylic acid ethyl ester gives N-((R)-2-tert-butoxycarbonylamino-1-methylethyl) -tetrahydropyran-4-carboxamide. The protecting group is removed with trifluoroacetic acid in ethanol at room temperature giving N-((R)-2-amino-1-methylethyl)-tetrahydropyran-4-carboxamide.

EXAMPLE 11 (S)-1-(4-(2-propoxyethoxy)phenoxy)-3-((S)-2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol

This compound is obtained as for Example 9 except that N-[(S)-2-amino-1-methylethyl]tetrahydropyran-4-carboxamide is used insteadof the racemate.

The amine reactant is obtained as for Example 10 from t-butoxycarbonyl-(L)-alaninamide instead of t-butoxycarbonyl-(D)-alaninamide. The following intermediates are obtained:

-(S)-2-tert-butoxycarbonylaminopropionitrile

-(S)-2-tert-butoxycarbonylaminopropylamine

-N-[(S)-2-tert-butoxycarbonylamino-1-methylethyl]tetrahydropyran-4-carboxamide

1]tetrahydropyran-4-carboxamide

-N[(S)-2-amino-1-methylethyl]tetrahydropyran-4-carboxamide

EXAMPLE 12 (RS)-1-(4-(2-propoxyethoxy)phenoxy)-3-((RS)-2-(tetrahydropyran-4-ylcarbonylamino)-1-methylethylamino)-2-propanol

This compound is obtained as for Example 9 except that (RS)-1-(2,3-epoxypropoxy)-4-(2-propoxyethoxy)benzene is used instead of the (S)-form.

EXAMPLE 13 (RS)-1-(4-(2-propoxyethoxy)phenoxy)-3-((S)-2-tetrahydropyran-4-ylcarbonylamino)-1-methylethylamino)-2-propanol

This compound is obtained as for Example 11 except that the (RS) epoxide ofExample 12 is used instead of the (S)-form.

EXAMPLE 14 (RS)-10(4-2-propoxyethoxy)phenoxy)-3-((R)-2-(tetrahydropyran-4-ylcarbonylamino)-1-methylethylamino)-2-propanol

This compound is obtained as for Example 10 except that the (RS) epoxide ofExample 12 is used instead of the (S)-form.

From the appropriate compounds of Formula III wherein R_(x) is ##STR12##and the appropriate compound of Formula IV the following compounds numbered15 to 32 of Formula I may be obtained in analogous manner to Examples 9 to 14.

    __________________________________________________________________________          Configuration                                                                  at carbon                                                                 Example                                                                             substituted by                 M.P.                                       No.  OH  R.sub.5                                                                            R.sub.1                                                                          R.sub.5                                                                           R                 (as base)                                  __________________________________________________________________________     15   (R,S)                                                                              (R) H CH.sub.3                                                                           ##STR13##        93-95° [α].sub.D.sup.20                                           = -5,88° (c = 1,3/methanol)         16   (R,S)                                                                              (R,S)                                                                              H CH.sub.3                                                                           ##STR14##        --                                         17   (R,S)                                                                              (S) H CH.sub.3                                                                           ##STR15##        --                                         18   (S) (R) H CH.sub.3                                                                           ##STR16##        --                                         19   (S) (S) H CH.sub.3                                                                           ##STR17##        --                                         20   (S) (R,S)                                                                              H CH.sub.3                                                                           ##STR18##        --                                         21   (R,S)                                                                              (R) H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub. 2 CH(CH.sub.3).sub.2                                                  84-86°                                                                  [α].sub.D.sup.20                                                         = 6,18°                                                                 (c = 1,6/methanol)                         22   (R,S)                                                                              (R,S)                                                                              H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   --                                         23   (R,S)                                                                              (S) H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   --                                         24   (S) (R) H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   --                                         25   (S) (S) H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   --                                         26   (S) (R,S)                                                                              H CH.sub.3                                                                          O(CH.sub.2).sub.2 OCH.sub.2 CH(CH.sub.3).sub.2                                                   --                                         27   (R,S)                                                                              (R) H CH.sub.3                                                                           ##STR19##        --                                         28   (R,S)                                                                              (R,S)                                                                              H CH.sub.3                                                                           ##STR20##        --                                         29   (R,S)                                                                              (S) H CH.sub.3                                                                           ##STR21##        --                                         30   (S) (R) H CH.sub.3                                                                           ##STR22##        --                                         31   (S) (S) H CH.sub.3                                                                           ##STR23##        --                                         32   (S) (R,S)                                                                              H CH.sub.3                                                                           ##STR24##        --                                         __________________________________________________________________________

EXAMPLE 33 1-(2-fluoro-4-hydroxyphenoxy)-3-[2-(tetrahydropyran-4-ylcarbonylamino)ethylamino]-2-propanol

(a) 4.0 g of 4-benzyloxy-2-fluorophenol is reacted with 10 g epichlorhydrinand 0.2 ml piperidine for 90 minutes at 100°. After removal of the volatile material, 40 ml tetrahydrofuran and 20 ml 2M NaOH is added. After1 hour stirring the solvent is evaporated and the residue partitioned between methylenechloride and water. The organic phase is purified over silica gel with toluene giving 4-benzyloxy-1-(2,3-epoxypropoxy)-2-fluorobenzene (colourless oil).

(b) 4.0 g of epoxide product obtained under (a) is refluxed for 4 hours with 3.1 g N-(2-aminoethyl)tetrahydropyran-4-carboxamide in 50 ml methanol. After removal of solvent the product is chromatographed over silica gel with methylene chloride/ethanol/ammonia 35% in water (90:9:1) giving (late fraction) 1-(4-benzyloxy-2-fluorophenoxy)-3-[2-tetrahydropyran-4-ylcarbonylamino)ethylamino]-2-propanol (M.P. 136°-138°).

(c) 3.75 g of product obtained under (b) is dissolved in 250 ml methanol and reduced with 10% palladium on charcoal at room temperature giving the title compound (M.P. 101°-104°-from ethanol/ether).

The compounds of the invention in free form or as the physiologically acceptable salt possess unique pharmacological activity and can be used astherapeutic agents in man.

In particular, the compounds possess beta adrenoceptor blocking activity asindicated by standard tests, for example, in the spontaneously beating guinea pig atrium (A. Bertholet et al., Postgraduate Medical Journal, 57, Suppl. 1, 9-17, 1981) they inhibit the positive chronotropic isoproterenoleffect at bath concentrations from about 10⁻⁹ to 10⁻⁸ M.

Thus, in the test above, the compounds have the following potencies expressed as a dose which doubles the concentration of isoproterenol needed to elicit a 50% increase in heart rate (i.e. ID₅₀).

    ______________________________________                                                      Guinea Pig Atrium                                                              Effective Molar Dose, M.                                          Example No.  (ID.sub.50)                                                       ______________________________________                                         1            1.2 × 10.sup.-7                                             2            5 × 10.sup.-8                                               3            8 × 10.sup.-8                                               4            5 × 10.sup.-8                                               5            3 × 10.sup.-8                                               6            2 × 10.sup.-8                                               7            2 × 10.sup.-7                                               8            7 × 10.sup.-8                                               9            4 × 10.sup.-8                                               10           3 × 10.sup.-8                                               11           1.6 × 10.sup.-7                                             15           3 × 10.sup.-8                                               21           7 × 10.sup.-8                                               Propranolol  3 × 10.sup.-9                                               Atenolol     2 × 10.sup.-7                                               Metoprolol   1.2 × 10.sup.-8                                             ______________________________________                                    

The beta adrenoceptor blocking activity in the heart can also be demonstrated in a whole animal model. For example, inhibition of isoproterenol induced tachycardia in the pithed rat show in vivo potenciesmany times higher than expected from their potencies in the guinea pig atria model and most of the potencies are comparable or higher than propranolol.

Thus, in the text above the following compounds exhibit effective beta-1 adrenoceptor blocking activity at the doses indicated below.

    ______________________________________                                                      Pithed Rat                                                                     Effective Dose (ID.sub.50)                                        Example No.  (ug/kg)                                                           ______________________________________                                         1            100                                                               2            20                                                                3            15                                                                4            20                                                                5            30                                                                6            30                                                                7            20                                                                8            20                                                                9            3                                                                 10           0.6                                                               11           20                                                                15           10                                                                21           5                                                                 Propranolol  20                                                                Atenolol     30                                                                Metoprolol   20                                                                ______________________________________                                    

The compounds are particularly useful as beta adrenoceptor blocking agents and can therefore be used for the prophylaxis and therapy of diseases which are commonly known to respond to blockade of beta adrenoceptors suchas those found in the heart. An example of such diseases are hypertension, angina pectoris, thyrotoxicosis, migraine and for the disturbances of the heart such as supraventricular tachycardia.

In addition the compounds have more marked and wider spread beneficial pharmacological properties than would be expected for compounds having this type of structure. In particular their activity is much more cardioselective than presently known from similar compounds.

They can be demonstrated in vitro in tracheal preparations of the guinea pig which are prepared according to standard procedures in which a portionof the tracheal muscle is allowed to relax under the influence of isoproterenol and in the presence of known concentrations of the compound to be tested.

In the test above potency in tracheal preparations is much less than in theatria as determined above. In the case of Examples, 2, 3, 4, 5, 6, 10 and 15 no blocking effect of the responses to isoproterenol are found in the trachea at concentrations as high as 3×10⁻⁵ mol/l, and are therefore considered to have virtually absolute selectivity or are specific for the cardiac beta 1 adrenoceptor. By comparison propranolol exerts a blocking effect in this model at a concentration of 1×10⁻⁸ mol/l. The selectivities of commonly known selective beta adrenoceptor blockers such as metoprolol and atenolol are, in this model, 5 and 20 respectively.

Thus the selectivity of these compounds is very much higher than standard drugs commonly available.

In the pithed rat preparation the compounds can produce a 100% inhibition of the effects of isoproterenol administered in the dose of 0.1 ug/kg i.v.on heart rate but have no effect on the blood pressure response to isoproterenol at doses as high as 3 mg/kg i.v.

In the conscious dog the maximum inhibitory effect of all compounds on the isoproterenol induced tachycardia at a dose of isoproterenol of 0.1 ug/kg i.v. is from 40-60% of that obtainable with non selective agents such as propranolol. The lack of complete blockade in the dog reflects the significant number of beta-2 cardiac adrenoceptors in this preparation which are not blocked by highly cardioselective compounds. The high or absolute selectivity of these compounds is of major importance in the treatment of hypertension where exacerbation of an asthmatic condition maybe precipitated by currently commercially available compounds.

The compounds with a bridging oxygen in the para position to the oxymethylene group also possess a degree of intrinsic sympathomimetic activity, a property which is useful in preventing undue bradycardia and helps to reduce the incidence of heart failure in patients with heart muscle disease. This property can be demonstrated as an increase in resting heart rate in a pithed rat preparation using standard procedures in which the maximum effect of cumulative doses of drug up to 3 mg/kg are observed. Examples 1 to 11,15 and 21 all showed increases in heart rate inthis pithed rat preparation and the maximum increases in heart rate ranged from 21-105 beats/min.

In the anaesthetised, vagotomized cat spinalised at the level of second cervical vertebrae the compounds exert an increase in cardiac contractile force at a dose of from about 20 to about 2,500 ug/kg i.v. as measured with a strain gauge arch sewn into the left ventricle. The effect may alsobe measured as a concentration dependent stimulation of the isolated spontaneously beating guinea pig atrium.

These compounds therefore, possess beta agonist as well as selective beta antagonist properties and are useful as cardiotonics, for example, for thetreatment of heart insufficiency, especially in situations where a positiveinotropic effect is desired without significant influence on blood pressure. The balance between the agonistic and antagonistic activities isparticularly favourable for compounds 9 and 33; the agonist component contributes to the cardiotonic activity whilst the antagonist component protects against an excessive increase in contractile force which may leadto arrhythmias.

Beta blockade is also useful in preventing large increases in heart rate and hence protecting the heart against formation of arrhythmic beats. Thusthese compounds are particularly useful for the treatment of disturbances of the heart rhythm such as supraventricular tachycardia.

These compounds also show the added advantage of lowering intraocular pressure when instilled as a buffered solution to the cornea of eyes. Thus, these compounds can therefore be used for the treatment of glaucoma.This property can be demonstrated using a standard test in rabbits. Reductions in intraocular pressure are observed by as much as 4 mm Hg overa two hour period.

The compounds are therefore useful as beta-1 adrenoceptor blocking agents, for example, for the prophylaxis and therapy of coronary artery diseases such as angina pectoris, conditions which are associated with sympathetic over stimulation, for example nervous heart complaints, myocardial infarction, hypertension, for the immediate treatment of migraine and for the treatment of glaucoma and thyrotoxicosis. In view of the antiarrhythmic effect they are useful as antiarrhythmics for the treatmentof disturbances in the heart rhythm such as supraventricular tachycardia.

For these uses described above, the dose will vary according to the substance used, the mode of administration and the desired treatment. In general however the dose required to treat hypertension and related coronary heart diseases with an oral formulation are obtained with a dailydosage of 0.5 to 5 mg/kg body weight; administration may be effected in one, two or three divided doses or as a sustained release form. For largermammals such as man the total daily dosage of these compounds is from about10 to 500 mg; suitable pharmaceutical formulations for oral administration generally contain from 2.5 to 250 mg of the compounds together with solid or liquid carriers and/or diluents known to persons skilled in the art.

For the treatment of glaucoma the dose is usually administered as sterile eye drops as a 0.5 to 2% solution in a buffer containing boric acid.

The compounds have more marked and wider spread beneficial pharmacological properties that would be expected from compounds having this type of structure. In particular, the compounds are characterised by being virtually cardiospecific which is not present in similar known compounds.

Of the compounds of the invention in optically active form in which the carbon atom in the 2 position of the 3-aminopropoxy side chain has the S-configuration are more pharmacologically active than the corresponding Renantiomer.

The preferred uses of the compound are against coronary heart diseases and for hypertension.

The compounds of the invention in free form or in the form of the pharmaceutically acceptable salts may be administered alone or in suitabledosage forms. The present invention also provides for a pharmaceutical composition comprising a compound of the invention, in free form or in salt form, probably an acid addition salt form, in association with a pharmaceutical carrier or diluent. Such forms, for example, a solution or a tablet, may be produced according to known methods. 

What is claimed is:
 1. A compound of Formula I, ##STR25## wherein A) R is O(CH₂)₂ O--R₃ and(a) R₁ and R₅ are hydrogen and R₃ is n-propyl, isobutyl, cyclopentylmethyl, benzyl or 2-(p-fluorophenyl)ethyl; (b) R₁ is fluorine and R₅ is hydrogen and R₃ is n-propyl; (c) R₁ is methyl and R₅ is hydrogen and R₃ is cyclopropylmethyl; (d) R₁ is cyano and R₅ is hydrogen and R₃ is n-propyl; (e) R₁ is hydrogen, R₅ is methyl and R₃ is alkyl of 2 to 5 carbon atoms, cycloalkylmethyl of 5 to 7 carbon atoms in the cycloalkyl part thereof or --(CH₂)_(n) --R' wherein n is 0, 1 or 2 and R' is phenyl or monofluorophenyl; or B) R is hydroxy, R₁ is fluorine and R₅ is hydrogen, or a physiologically hydrolysable ester thereof.
 2. A compound as claimed in claim 1, in the optically active (S)-form at the carbon atom in the 2-position of the 3-aminopropoxy moiety.
 3. A compound as claimed in claim 1, wherein, when R⁵ is methyl, said compound is in the R configuration at the carbon atom at which R⁵ is substituted.
 4. A compound as claimed in claim 1, which is a racemic mixture.
 5. A compound as claimed in claim 1, of the Formula E ##STR26## where R, R₁, and R₅ are as defined in claim 1 and R_(e) is alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono---or independently disubstituted in the phenyl ring by halogen of atomic number of from 9 to 35, or mono---or independently di---or independently tri---substituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.
 6. 1-(2-Fluoro-4-(2-propoxyethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino) -2-propanol,1-(4-(2-propoxyethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino(-2-propanol, 1-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino) -2-propanol, 1-(4-(2-cyclopentylmethoxyethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino)-2-propanol, 1-(4-(2-(2-(4'-fluorophenyl)ethoxy)ethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl -carbonylamino)ethylamino)-2-propanol, 1-(2-methyl-4-(2-cyclopropylmethoxyethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino)-2propanol, 1-(4-(2-phenylmethoxyethoxy)phenoxy)-3(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino)-2-propanol, 1-(2-cyano-4-(2-propoxyethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)ethylamino) -2propanol, (S)-1-(4-(2-propoxyethoxy)phenoxy)-3-(R,S)-(2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol, (S)-1-(4-(2-propoxyethoxy)phenoxy)-3-(R)-(2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol, (S)-1(4-(2-propoxyethoxy)phenoxy)-3-(S)-(2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol, (S) -1-(4-(2-cyclopentylmethoxyethoxy)phenoxy)-3-(R)-(2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2-propanol, (S)-1-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-3-(R)-(2-(tetrahydropyran-4-yl-carbonylamino) -1-methylethylamino)-2-propanol, 1-(4-(2-(2-(4'-fluorophenyl)ethoxy)ethoxy)phenoxy)-3-(2-(tetrahydropyran-4-yl-carbonylamino)-1-methylethylamino)-2propanol, 1-(2-fluoro-4-hydroxyphenoxy)-3-(2-tetrahydropyran-4-yl-carbonylamino)ethylamino)-2-propanol,or a physiologically hydrolysable ester thereof.
 7. A pharmaceutical composition characterised in that it comprises a compound of any one of claims 1, 2 or 17 in free form or in a pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.
 8. A method of treating coronary diseases, which comprises administering a therapeutically effective amount of a compound of any one of claims 1, 2 or 17 in free form or in a pharmaceutically acceptable salt form.
 9. A method of treating heart rhythm disorders which comprises administering a therapeutically effective amount of a compound of any one of claims 1, 2 or 6 in free form or in a pharmaceutically acceptable salt form. 